Some of the common approaches to cancer treatment include surgery, radiation therapy, and chemotherapy. Radiation therapy and chemotherapy are effective if they are capable of killing the tumor cells; i.e., when they act as cytotoxic agents. Typically, the response to radiation therapy or chemotherapy is monitored by magnetic resonance imaging (MRI) of the tumor, wherein a decrease in tumor size is indicative of positive response to treatment.
Cytotoxic therapies rely on disrupting the DNA and RNA of malignant cells. Radiation creates DNA strand breaks and aberrations. Examples of lethal aberrations are the ring and dicentric chromosomal aberrations, and the anaphase bridge chromatid aberration. Hall, E. J., Ch 2 in Radiobiology for the Radiologist, 5th ed., Lippincott, Williams and Wilkins (2000). Cytotoxic agents or drugs generally alter DNA and RNA synthesis or functions, e.g., forming cross links between DNA strands (alkylating agents and platinum analogs); inhibiting DNA-dependent RNA polymerase (streptomycin drugs); blocking production of mitotic spindles (vinca alkaloids); and preventing disassociation of drug treated spindles (taxans). Hall, E. J., Ch 27, supra.
Cytotoxic agents induce apoptosis, a programmed cell death. Apoptosis is under the control of two signaling pathways. One pathway utilizes “death receptors” on the cancer cell membrane. Fas and tumor necrosis factor (TNF) receptors can be activated by cytotoxic drugs, such as adriamycin, forming caspase-8 thereby initiaing a protease cascade that cleaves cellular targets and results in apoptosis cell death. The second pathway is initiated by cellular stress, such as DNA damage from either radiation or chemotherapeutic agents. The DNA strand breaks are sensed by kinases that activate p53 (a tumor suppressor protein) resulting in the bax gene releasing cytochrome c from the mitochondria. Cytochrome c activates caspase-9 and downstream caspases causing apoptosis. Apoptosis links programmed cell death to DNA damage. Schmitt, C. A., et al., J. Path. 187, 127-137 (1999).
Unfortunately, tumors can be resistant to a class of chemotherapeutic agents, or develop resistance during the prolong exposure to a cytotoxic drug. Untreated tumors may have a mutation in p53, a tumor suppressor protein, preventing the release of cytochrome c from the mitochondria and thereby blocking apoptosis. Schmitt, et al., supra, and Bunz, F., et al., J. Clin. Invest. 104, 263-269 (1999). Drug resistance may develop during treatment by up-regulating the multiple drug resistance (mdr) gene that extrudes the drug out of the cell. Drug resistance may also develop the malignant cells increase intraceullular glutathione. Hall, E. J., Ch 27, supra.
Radiation resistance develops in hypoxic tumors because some DNA strand breaks are repaired. Radiation sensitivity is maintained in oxygenated tumors with oxygen forming peroxides that react with the DNA strand breaks preventing their repair. Hall, E. J., Ch 6 supra.
Cytotoxic resistance is now monitored by obtaining sequential contrast CT/MR studies at 3-12 month intervals. Resistance to treatment is identified by an increase in tumor size and an increase in enhancement (angiogenesis) of the tumor following the treatment. Therapeutic response is documented by decrease in tumor size and decrease in tumor enhancement. The decrease in size documents apoptosis with loss of cellularity. In many cases, a detectable change in tumor size is observed only after a significant long period of time, for example after treatment for a period of 3 months or more. Such long periods of time could be harmful to the patient for during this long period of time, tumor cells could multiply and/or metastasize, and lead to worsening the patient's condition.
The foregoing shows that there exists a need for a method where an early cytotoxic treatment response can be monitored. Accordingly, the present invention provides such a method. This and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.